As the age of people living with HIV has been rising steadily due to the success of antiretroviral therapy (ART), and continued new infections, the number of people with HIV in the US is now 1.2 million and continues to rise. Since most older adults living with HIV were infected as young adults or in middle age, long-term effects of HIV and ART are now emerging. HIV/ART-associated comorbidities represent a major challenge for HIV-infected individuals. Of noninfectious comorbidities, coronary artery disease (CAD) has become one of leading causes of death among older people with HIV infection. In addition to CAD traditional risk factors, HIV and ART, cocaine use has been shown to be associated with CAD. In 1999, we received the first NIH grant in the US to investigate the effects of HIV and cocaine use on subclinical atherosclerosis, specifically HIV- associated cardiovascular comorbidity. Since then, 4 NIDA-funded studies by this team were conducted and a cohort of study participants, with/without HIV infection, with/without ART and with/without cocaine use, has been established and followed in Baltimore, Maryland for 17 consecutive years. Pursuing the goal of examining the individual and combined effects of HIV infection, long-term exposure to ART, chronic cocaine use, and other factors on subclinical CAD, we found that cocaine use may induce/accelerate subclinical CAD and other HIV-associated comorbidities. We recently identified several high priority research questions/hypotheses that deserve to be explored thorough collaborations with other investigators: (1) coronary plaque volume may be more sensitive to quantify factors associated with coronary plaque burden, (2) telomere length may be associated with HIV, cocaine use and aging, (3) Troponin T may be a maker for the degree of coronary plaque burden, and (4) homocysteine may be a potentially useful biomarker for HIV/cocaine associated comorbidities. The central objective for this U01 is to further examine whether and how cocaine use influences the HIV/ART- associated CAD and other comorbidities. The specific aims of this proposed study are: (1) to maintain and expand our existing cohort involving HIV/ART and cocaine-associated cardiovascular and other comorbidities as a platform for high priority research and as a platform for other scientific collaborations; (2) to examine longitudinally the effects of HIV, chronic cocaine use, and prolonged ART exposure on the presence, development and progression of CCTA-defined subclinical/clinical CAD, (3) to investigate whether cocaine use exacerbates the HIV-associated decline in cognitive function in HIV-infected cocaine users, (4) to investigate whether HIV and cocaine are associated with telomere shortening, and (5) to examine interrelationships between homocysteine (Hcy) and HIV/ART/cocaine-associated comorbidities. All the hypotheses proposed in this application have not been tested and are crucial to the scientific field of HIV/AIDS and substance abuse. The proposed study will make unique contributions to a better understanding of whether and how drug abuse exacerbates cardiovascular and other comorbidities in those with HIV and substance use disorder.